SYSTEMIC AD-FLT3L DELIVERY COUPLED WITH INTRATUMORAL AD-HSV1-TK ERADICATES INTRACRANIAL GBM AND GENERATES LONG TERM IMMUNOLOGICAL MEMORY IN A SYNGENEIC RAT MODEL

MUHAMMAD; CANDOLFI; YAGIZ; PUNTEL; SANDERSON; LIU; KROEGER; LOWENSTEIN; CASTRO

Dallas, Texas, USA

Congreso; Society for Neuro-Oncology; 2008

240. SYSTEMIC AD-FLT3L DELIVERY COUPLED WITH INTRATUMORAL AD-HSV1-TKERADICATES INTRACRANIAL GBM AND GENERATES LONG TERM IMMUNOLOGICALMEMORY IN A SYNGENEIC RAT MODELA.K.M. Ghulam Muhammad, MBBS, PhD; Marianela Candolfi, VMD, PhD; Kader Yagiz, PhD; MarianaPuntel; Nicholas Sanderson; Chunyan Liu; Kurt Kroeger; WS Nichols; Pedro Lowenstein; Maria CastroINTRODUCTION: Aiming to make the combined gene therapy for GBM less invasive, the adenoviralvector (Ad) expressing fms-like tyrosine kinase 3 ligand (Flt3L) was delivered systemically into GBMbearing Lewis rats. METHODS: Six days following GBM implantation into the striatum, intravenouspre-dosing with empty Ad (Ad-0; 4x10e10vp) was performed to saturate the liver reticulo-endotheliumsystem/Kuffer cells. Within 4~6h, Ad-Flt3L (5x10e9pfu) was injected via the tail vein followed byintratumoral delivery of Ad-TK (1x10e8pfu). The controls received either Ad-Flt3L or Ad-0 in the tailvein followed by intratumoral saline or Ad-TK. After 24h, ganciclovir was injected daily for 10d.RESULTS: GBM bearing control rats succumbed by day 22, whereas, ~80% of the Ad-Flt3L(systemic)+Ad-TK (intratumoral) treated rats survived >60d (P<0.01; log-rank test). The long-termsurvivors were rechallenged with 4,500 GBM cells in the brain and 70% of them survived long-term(>120d). Serum biochemistry and H&E stained liver specimens did not reveal hepatotoxicity. Nisslstaining on Ad-Flt3L+Ad-TK treated long-term survivors displayed no residual tumor.Immunohistochemistry against myelin basic protein or tyrosine hydroxylase showed absence ofdemyelination or overt striatal damage, respectively; CD68+ macrophages, few CD8+ T cells, and MHCII immunopositive cells were detected. Positive delayed type hypersensitivity reaction in long-termsurvivors indicated the presence of systemic anti-GBM cellular immune response. CONCLUSION:These findings highlight the potential of systemic delivery of Ad-Flt3L in the current clinical setting inwhich GBM antigens would become available from dead/dying GBM tumor cells due to surgery,radiotherapy and or chemotherapy in human GBM patients. Hence the novel treatment strategy shallrender our combined gene therapy strategy even safer and less invasive. In conclusion, gene therapyaimed at mounting immune stimulation using systemic Ad-Flt3L coupled with conditional cytotoxic treatment (Ad-TK/GCV) elicits tumor regression and immunological memory inhibiting tumor recurrencehighlighting its prospect as a novel adjuvant treatment strategy for human GBM.